DNMT3A Stability Is Maintained by Ubiquitin-Specific Peptidase 11 (USP11) and Sumoylation Countering Degradation.

DNA methyltransferase 3A (DNMT3A) plays crucial roles in hematopoiesis and mammalian development. DNMT3A protein instability has been associated with several diseases such as MDS, AML and Tatton-Brown-Rahman syndrome. Here we report, DNMT3A stability is maintained by deubiquitinating enzyme USP11 countering degradation by CUL4-DCAF8 E3 ligase. DNMT3A localization changes caused by certain unstable DNMT3A mutations, which could be considered one of the losses of function of DNMT3A. The mislocalization is partially rescued by E1 enzyme inhibition or stable USP11 expression lines. Interestingly, we show that USP11 enhances DNMT3A SUMOylation by promoting the interaction between DNMT3A and SUMO E3 Ligases, and DNMT3A SUMOylation also essential for maintaining DNMT3A protein stability and DNMT3A DNA Mtase activity. Our results reveal the mechanism for DNMT3A protein turnover through USP11, and the mechanism essential for DNMT3A function, as well as a therapeutic approach for several diseases causing DNMT3A protein instability.